Cancers of the gastrointestinal (GI) tract are some of the most common cancers in Europe and the US. Unfortunately, both upper and lower GI cancer remain relatively asymptomatic until late in the natural history of the disease. Upper GI cancer symptoms are often non-specific and by the time that ‘alarm symptoms’ such as dysphagia, abdominal pain, vomiting, weight loss, or anemia are present, the cancer is often at an advanced stage and the prognosis is poor. Therefore improving the survival diagnosis at an early stage is of utmost importance.
Treatment of patients with upper gastrointestinal (GI) cancers has not made the same positive progress as treatment of colorectal cancer during the last two decades. Pancreatic cancer is the 4th most common cause of cancer death in men and women in US with approximately 34,000 estimated deaths in 2008. The incidence of gastic cancer is falling in US and Western Europe (1-3) and the estimated death in US in 2008 is 10,880 (1). The incidence of Gallbladder cancer and other extrahepatic biliary cancers are unchanged and there is 3,340 estimated death of this type of cancer in 2008 in US (1).
Operation is the only potentially curable treatment for upper GI cancers. A major problem is that 85% of patients with pancreatic cancer have already locally advanced or metastatic disease at time of diagnosis, and their median survival time is only 6 months and <10% are alive after 1 year. For patients with gastric cancer and biliary cancers there is an ongoing tendency towards better survival, because more patients have a lower stage at time of diagnosis with equivalent better chance of successful surgery, however <50% are alive after 1 year (and 24% after 5 years, US) (1-3). The treatment options for patients that can not be radically operated are palliative radio- or chemotherapy, with only poor response rates (4-6).
Administering a treatment for a given gastrointestinal cancer is typically based on the diagnosis of the disease, and occasionally on the severity of the disease disregarding the physiology of the individual suffering from the particular type of gastrointestinal cancer. Likewise, the continued treatment and monitoring of a gastrointestinal cancer is often according to a predetermined schedule, without paying too much attention to the individual patient.
Although, there might in the future be more effective chemotherapy regimes or new biological treatments, the best way to improve survival for patients with upper GI cancers is to diagnose the patients at an earlier stage. Identification of new biomarkers is a step in this direction.
A single marker or method that would facilitate selecting between treatments of varying efficacy and/or monitoring the progression or determining the stage of a gastrointestinal cancer prior to, during and following administration of a given treatment would greatly improve the ease with which these selection and monitoring processes occur today.
Carbohydrate (CA) 19-9 is the only routinely used biomarker in patients with pancreatic cancer, but has no value for screening or determining operability, and CA 19-9 is not useful in patients with gastric cancer or biliary cancer. Serum CA 19-9 is elevated in 70-80% of patients with pancreatic cancer, highest in metastatic disease, and high serum CA 19-9 is associated with short survival (7,8). However, 10-20% of patients with benign pancreatic diseases have also elevated serum CA 19-9. It is recommended to measure serum CA19-9 in patients with locally advanced metastatic pancreatic cancer at start of treatment and every 1-3 months during treatment. Elevations in serum CA 19-9 may reflect progression and should be confirmed with e.g. Computerized Tomography scanning (7,8).
The advantages associated with choosing the best possible treatment is not limited to be of benefit for the health of the individual suffering from the gastrointestinal cancer; it is also of benefit to the economy of the individual and the hospital/the economy of the society at large.
Certain markers are known to be associated with specific cancer types; examples hereof include HER2 which is a marker of certain forms of breast cancer and EGFR which has been linked to e.g. colorectal cancer, pancreas cancer, head and neck cancer, lung cancer and glioblastoma multiforme.
Cetuximab (Erbitux®) is a chimeric mouse/human monoclonal antibody against the epidermal growth factor receptor (EGFR) and approved for use in patients with metastatic colorectal cancer and squamous cell carcinoma of the head and neck. Cetuximab is given as intravenous injection every week (400 mg/m2 initial dose followed by 250 mg/m2 every week) or every second week (400 mg/m2 initial dose followed by 500 mg/m2 every second week) as monotherapy or in combination with standard chemotherapy for metastatic colorectal cancer like irinotecan, oxaliplatin, and fluorouracil (5-FU) in combination with leucovorin or in combination with radiation therapy in patients with rectal cancer or squamous cell carcinoma of the head and neck (1-19).
Panitumumab (Vectibix®) is a fully human monoclonal antibody against the EGFR and approved for use in patients with metastatic colorectal cancer. Panitumumab is given as intravenous injection every second week (6 mg/kg) as monotherapy or in combination with standard chemotherapy for metastatic colorectal cancer (9, 20-23).
Recent data have demonstrated that patients with metastatic colorectal cancer and a mutation in the Kirsten ras (KRAS) gene, an oncogene downstream from the EGFR, have no effect of treatment with cetuximab and panitumumab. The KRAS encoded protein is a member of the small GTPAse superfamily, and a single amino acid substitution in the KRAS gene results in an activating mutation. Since summer 2008 only colorectal cancer patients with KRAS wild type are recommended to be treated with cetuximab and panitumumab. KRAS is mutated in approximately 30% to 45% of all colorectal tumors, resulting in a constitutively active EGF signalling pathway (6-9, 11, 12, 13, 14, 21, 24, 25, 26). The identification of KRAS as a predictive biomarker of response to anti-EGFR therapy has obvious benefits. First, close to half of patients with metastatic colorectal cancer will avoid unnecessary exposure to an ineffective therapy that has the potential to cause significant toxicities. Second, the potential cost savings to the health care system are profound, approximately $ 600 million each year in USA (8 weeks of treatment with cetuximab cost approximately $ 19,000).
However, KRAS mutations are not the only factor influencing response to anti-EGFR antibodies. Approximately 25% to 40% of patients with KRAS wild type do not respond to anti-EGFR antibody. Approximately 10% of these patients have mutations in the BRAF gene. This causes a change in the BRAF protein that can increase growth and spread of cancer cells. BRAF is an isoform of RAF. RAF proteins are intermediate to RAS and MAPK in the cellular proliferation pathway. RAF proteins are typically activated by RAS via phosphorylation, and activated RAF proteins in turn activate MAPK via phosphorylation. Furthermore some patients with KRAS wild type have a loss of protein expression of PTEN, a tumor supressor gene, and some have low expression of either amphiregulin (AREG) or epiregulin (EREG) and these patients have less response to cetuximab (9, 12, 26, 27, 28, 29). These recent studies need to be validated and it is not yet recommended to test for BRAF mutations or expression of PTEN, AREG or EREG before treatment with cetuximab or panitumumab. Even if both KRAS and e.g. BRAF was used in order to predict the responsiveness to such treatment about 40% KRAS wildtype patients remain that are unresponsive towards the treatment (26,29).
Thus identification of other predictive biomarkers is imperative to improve the selection of patients with GI cancers such as for example metastatic colorectal cancer for treatment with antibodies against EGFR or for the treatment with other biologic agents such as e.g. antibodies against VEGF.
An ideal biomarker for GI cancer should have the quality of being able to identify the patients at an early stage and help the surgeon select the right patients for operation. The biomarker could also be useful for monitoring the disease recurrence/progression after operation or chemotherapy and help the oncologist to evaluate the effect of chemotherapy in order to give a more individual treatment. There is no such biomarker for patients with GI cancer and especially upper GI cancer.
Administering the best possible treatment for each individual patient with gastrointestinal cancer would improve the efficacy of any treatment whether it involves administration of medicaments, surgery, or other and independent of whether the treatment given is prophylactic, curative or ameliorative. A classification of the individuals suffering from a gastrointestinal cancer according to survival prognosis and time to progression would be of assistance in determining the best possible treatment, improve the effect of an administered treatment, improve the survival rate, lower relapse risks, and heighten the quality of life following the outbreak of a gastrointestinal cancer.
Likewise, monitoring the treatment administered to any individual patient depending upon the progression and/or state of their disease would be of assistance in determining the most effective immediate and follow-up treatment, and be of guidance when counseling on e.g. lifestyle chances required subsequent to the occurrence of a gastrointestinal cancer.